Talk:Musculoskeletal System - Joint Development

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Cite this page: Hill, M.A. (2020, May 31) Embryology Musculoskeletal System - Joint Development. Retrieved from


Carrera-Pinzón AF, Márquez-Flórez K, Kraft RH, Ramtani S & Garzón-Alvarado DA. (2019). Computational model of a synovial joint morphogenesis. Biomech Model Mechanobiol , , . PMID: 31863216 DOI.

Computational model of a synovial joint morphogenesis Abstract Joints enable the relative movement between the connected bones. The shape of the joint is important for the joint movements since they facilitate and smooth the relative displacement of the joint's parts. The process of how the joints obtain their final shape is yet not well understood. Former models have been developed in order to understand the joint morphogenesis leaning only on the mechanical environment; however, the obtained final anatomical shape does not match entirely with a realistic geometry. In this study, a computational model was developed with the aim of explaining how the morphogenesis of joints and shaping of ossification structures are achieved. For this model, both the mechanical and biochemical environments were considered. It was assumed that cartilage growth was controlled by cyclic hydrostatic stress and inhibited by octahedral shear stress. In addition, molecules such as PTHrP and Wnt promote chondrocyte proliferation and therefore cartilage growth. Moreover, the appearance of the primary and secondary ossification centers was also modeled, for which the osteogenic index and PTHrP-Ihh concentrations were taken into account. The obtained results from this model show a coherent final shape of an interphalangeal joint, which suggest that the mechanical and biochemical environments are crucial for the joint morphogenesis process. KEYWORDS: Cartilage growth; Development; Finite element methods; Joint; Joint development; Joint morphogenesis; Synovial joints PMID: 31863216 DOI: 10.1007/s10237-019-01277-4

Bechtold TE, Kurio N, Nah HD, Saunders C, Billings PC & Koyama E. (2019). The Roles of Indian Hedgehog Signaling in TMJ Formation. Int J Mol Sci , 20, . PMID: 31847127 DOI.

The Roles of Indian Hedgehog Signaling in TMJ Formation

Abstract The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and articular cartilage in long bones. Condylar cartilage is organized in distinct cellular layers that include a superficial layer that produces lubricants, a polymorphic/progenitor layer that contains stem/progenitor cells, and underlying layers of flattened and hypertrophic chondrocytes. Uniquely, progenitor cells reside near the articular surface, proliferate, undergo chondrogenesis, and mature into hypertrophic chondrocytes. During the past decades, there has been a growing interest in the molecular mechanisms by which the TMJ develops and acquires its unique structural and functional features. Indian hedgehog (Ihh), which regulates skeletal development including synovial joint formation, also plays pivotal roles in TMJ development and postnatal maintenance. This review provides a description of the many important recent advances in Hedgehog (Hh) signaling in TMJ biology. These include studies that used conventional approaches and those that analyzed the phenotype of tissue-specific mouse mutants lacking Ihh or associated molecules. The recent advances in understanding the molecular mechanism regulating TMJ development are impressive and these findings will have major implications for future translational medicine tools to repair and regenerate TMJ congenital anomalies and acquired diseases, such as degenerative damage in TMJ osteoarthritic conditions. KEYWORDS: Ihh; PTHrP; TMJ; articular disc; osteoarthritis; synovial joint PMID: 31847127 PMCID: PMC6941023 DOI: 10.3390/ijms20246300


Precise spatial restriction of BMP signaling in developing joints is perturbed upon loss of embryo movement

Development. 2018 Mar 12;145(5). pii: dev153460. doi: 10.1242/dev.153460.

Singh PNP1, Shea CA2, Sonker SK1, Rolfe RA2, Ray A1, Kumar S1, Gupta P1, Murphy P3, Bandyopadhyay A4.


Dynamic mechanical loading of synovial joints is necessary for normal joint development, as evidenced in certain clinical conditions, congenital disorders and animal models where dynamic muscle contractions are reduced or absent. Although the importance of mechanical forces on joint development is unequivocal, little is known about the molecular mechanisms involved. Here, using chick and mouse embryos, we observed that molecular changes in expression of multiple genes analyzed in the absence of mechanical stimulation are consistent across species. Our results suggest that abnormal joint development in immobilized embryos involves inappropriate regulation of Wnt and BMP signaling during definition of the emerging joint territories, i.e. reduced β-catenin activation and concomitant upregulation of pSMAD1/5/8 signaling. Moreover, dynamic mechanical loading of the developing knee joint activates Smurf1 expression; our data suggest that Smurf1 insulates the joint region from pSMAD1/5/8 signaling and is essential for maintenance of joint progenitor cell fate. KEYWORDS: Articular cartilage; Immobilization; Joint development; Mechanoregulation; Mechanosensitivity; Muscle contraction; Wnt/BMP signaling PMID: 29467244 DOI: 10.1242/dev.153460

Development of the human shoulder joint during the embryonic and early fetal stages: anatomical considerations for clinical practice

J Anat. 2018 Mar;232(3):422-430. doi: 10.1111/joa.12753. Epub 2017 Nov 28.

Hita-Contreras F1, Sánchez-Montesinos I2, Martínez-Amat A1, Cruz-Díaz D1, Barranco RJ1, Roda O2.


Although several studies have been published regarding the morphology and anatomical variations of the human shoulder joint, most have dealt with adult individuals. Those looking into the development of the joint have been focused on specific structures or have observed specimens in advanced gestational stages. The goal of this paper is to perform a complete analysis of the embryonic and early fetal development of the elements in the shoulder joint, and to clarify some contradictory data in the literature. In our study, serial sections of 32 human embryos (Carnegie stages 16-23) and 26 fetuses (9-13 weeks) were analyzed. The chondrogenic anlagen of the humerus and the medial border of the scapula can be observed from as early as Carnegie stage 17, whereas that of the rest of the scapula appears at stage 18. The osteogenic process begins in week 10 for the humeral head and week 11 for the scapula. At stage 19 the interzone becomes apparent, which will form the glenohumeral joint. In the next stage the glenohumeral joint will begin delaminating and exhibiting a looser central band. Denser lateral bands will join the humeral head (caput humeri) and the margins of the articular surface of the scapula, thus forming the glenoid labrum, which can be fully appreciated by stage 22. In 24-mm embryos (stage 21) we can observe, for the first time, the long head of the biceps tendon (which is already inserted in the glenoid labrum by week 9), and the intertubercular sulcus, whose depth is apparent since week 12. Regarding ligamentous structures, the coracohumeral ligament is observed at the end of Carnegie stage 23, whereas the primitive glenohumeral ligament already appeared in week 10. The results of this study provide a detailed description of the morphogenesis, origin and chronological order of appearance of the main intrinsic structures of the human shoulder joint during late embryonic and early fetal development. We expect these results to help explain several functional aspects of the shoulder joint, and to clarify some contradictory data in the literature regarding this complex anatomical and biomechanical structure, helping future researchers in their efforts. KEYWORDS: biceps; chondrogenesis; coracohumeral; development; embryology; fetal; glenohumeral PMID: 29193070 DOI: 10.1111/joa.12753


Mechanobiological simulations of prenatal joint morphogenesis

J Biomech. 2014 Mar 21;47(5):989-95. doi: 10.1016/j.jbiomech.2014.01.002. Epub 2014 Jan 10.

Giorgi M1, Carriero A1, Shefelbine SJ2, Nowlan NC3.


Joint morphogenesis is the process in which prenatal joints acquire their reciprocal and interlocking shapes. Despite the clinical importance of the process, it remains unclear how joints acquire their shapes. In this study, we simulate 3D mechanobiological joint morphogenesis for which the effects of a range of movements (or lack of movement) and different initial joint shapes are explored. We propose that static hydrostatic compression inhibits cartilage growth while dynamic hydrostatic compression promotes cartilage growth. Both pre-cavitational (no muscle contractions) and post-cavitational (with muscle contractions) phases of joint development were simulated. Our results showed that for hinge type motion (planar motion from 45° to 120°) the proximal joint surface developed a convex profile in the posterior region and the distal joint surface developed a slightly concave profile. When 3D movements from 40° to -40° in two planes were applied, simulating a rotational movement, the proximal joint surface developed a concave profile whereas the distal joint surface rudiment acquire a rounded convex profile, showing an interlocking shape typical of a ball and socket joint. The significance of this research is that it provides new and important insights into normal and abnormal joint development, and contributes to our understanding of the mechanical factors driving very early joint morphogenesis. An enhanced understanding of how prenatal joints form is critical for developing strategies for early diagnosis and preventative treatments for congenital musculoskeletal abnormalities such as developmental dysplasia of the hip. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved. KEYWORDS: Cartilage growth; Chondrogenesis; Computational model; Joint biomechanics; Joint shape

PMID 24529755


Development of articular cartilage and the metaphyseal growth plate: the localization of TRAP cells, VEGF, and endostatin

J Anat. 2011 Apr 3. doi: 10.1111/j.1469-7580.2011.01377.x. [Epub ahead of print]

Stempel J, Fritsch H, Pfaller K, Blumer MJ.

Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria Division of Histology and Embryology, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria.

Abstract During long bone development the original cartilaginous model in mammals is replaced by bone, but at the long bone endings the avascular articular cartilage remains. Before the articular cartilage attains structural maturity it undergoes reorganization, and molecules such as vascular endothelial growth factor (VEGF) and endostatin could be involved in this process. VEGF attracts blood vessels, whereas endostatin blocks their formation. The present study therefore focused on the spatio-temporal localization of these two molecules during the development of the articular cartilage. Furthermore, we investigated the distribution of the chondro/osteoclasts at the chondro-osseous junction of the articular cartilage with the subchondral bone. Mice served as our animal model, and we examined several postnatal stages of the femur starting with week (W) 4. Our results indicated that during the formation of the articular cartilage, VEGF and endostatin had an overlapping localization. The former molecule was, however, down-regulated, whereas the latter was uniformly intensely localized until W12. At the chondro-osseous junction, the number of tartrate-resistant acid phosphatase (TRAP)-positive chondro/osteoclasts declined with increasing age. Until W3 the articular cartilage was not well organized but at W8 it appeared structurally mature. At that time only a few TRAP cells were present, indicative of a low resorptive activity at the chondro-osseous junction. Subsequently, we examined the metaphyseal growth plate that is closed when skeletal maturity is attained. Within its hypertrophic zone, localization of endostatin and VEGF was observed until W6 and W8, respectively. At the chondro-osseous junction of the growth plate, chondro/osteoclasts remained numerous until W12 to allow for its complete resorption. According to former findings, VEGF is critical for a normal skeleton development, whereas endostatin has almost no effect on this process. In conclusion, our findings suggest that both VEGF and endostatin play a role in the structural reorganization of the articular cartilage and endostatin may be involved in the maintenance of its avascularity. In the growth plate, however, endostatin does not appear to counteract VEGF, allowing vascular invasion of hypertrophic cartilage and bone growth.

© 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.

PMID: 21457260


Postnatal development of depth-dependent collagen density in ovine articular cartilage

BMC Dev Biol. 2010 Oct 22;10:108.

van Turnhout MC, Schipper H, van Lagen B, Zuilhof H, Kranenbarg S, van Leeuwen JL.

Experimental Zoology Group, Department of Animal Sciences, Wageningen University, PO Box 338, 6700 AH, Wageningen, The Netherlands.


BACKGROUND: Articular cartilage (AC) is the layer of tissue that covers the articulating ends of the bones in diarthrodial joints. Adult AC is characterised by a depth-dependent composition and structure of the extracellular matrix that results in depth-dependent mechanical properties, important for the functions of adult AC. Collagen is the most abundant solid component and it affects the mechanical behaviour of AC. The current objective is to quantify the postnatal development of depth-dependent collagen density in sheep (Ovis aries) AC between birth and maturity. We use Fourier transform infra-red micro-spectroscopy to investigate collagen density in 48 sheep divided over ten sample points between birth (stillborn) and maturity (72 weeks). In each animal, we investigate six anatomical sites (caudal, distal and rostral locations at the medial and lateral side of the joint) in the distal metacarpus of a fore leg and a hind leg.

RESULTS: Collagen density increases from birth to maturity up to our last sample point (72 weeks). Collagen density increases at the articular surface from 0.23 g/ml ± 0.06 g/ml (mean ± s.d., n = 48) at 0 weeks to 0.51 g/ml ± 0.10 g/ml (n = 46) at 72 weeks. Maximum collagen density in the deeper cartilage increases from 0.39 g/ml ± 0.08 g/ml (n = 48) at 0 weeks to 0.91 g/ml ± 0.13 g/ml (n = 46) at 72 weeks. Most collagen density profiles at 0 weeks (85%) show a valley, indicating a minimum, in collagen density near the articular surface. At 72 weeks, only 17% of the collagen density profiles show a valley in collagen density near the articular surface. The fraction of profiles with this valley stabilises at 36 weeks.

CONCLUSIONS: Collagen density in articular cartilage increases in postnatal life with depth-dependent variation, and does not stabilize up to 72 weeks, the last sample point in our study. We find strong evidence for a valley in collagen densities near the articular surface that is present in the youngest animals, but that has disappeared in the oldest animals. We discuss that the retardance valley (as seen with polarised light microscopy) in perinatal animals reflects a decrease in collagen density, as well as a decrease in collagen fibril anisotropy.

PMID: 20969753

"Hunziker et al. [47] showed that AC grows appositionally. The superficial zone supplies the stem cells for AC growth. Daughter cells that are displaced horizontally, remain confined to the superficial zone and replenish the stem-cell pool and affect lateral growth. Daughter cells that move vertically downwards form a zone with a rapidly dividing and proliferating pool of cells for rapid clonal expansion. This zone affects longitudinal growth and is located at the transitional and upper deep layer of AC [47]. The location (distance from the articular surface) of the collagen density valley in our study appears to coincide with the zone of rapidly dividing daughter cells in the study by Hunziker et al. [47]. Hunziker et al. further showed that the proliferation activity of this pool of cells decreased with age and had ceased when AC thickness stabilised. The valley in collagen density that we observe in our study also gradually disappears with age, and also stabilises when cartilage thickness stabilises (36 weeks, figure 5c). These similarities in the spatial and temporal patterns of cell proliferation and the presence of a collagen density valley, suggest a relationship between the cell activity and collagen production in this zone. Dedicated investigations will be required to show whether or not such a relationship exists."


The structural architecture of adult mammalian articular cartilage evolves by a synchronized process of tissue resorption and neoformation during postnatal development

Osteoarthritis Cartilage. 2007 Apr;15(4):403-13. Epub 2006 Nov 13.

Hunziker EB, Kapfinger E, Geiss J.

University of Bern, ITI Research Institute for Dental and Skeletal Biology, Murtenstrasse 35, PO Box 54, Bern, Switzerland. Erratum in:

Osteoarthritis Cartilage. 2007 Sep;15(9):1099.


OBJECTIVE: During postnatal development, mammalian articular cartilage acts as a surface growth plate for the underlying epiphyseal bone. Concomitantly, it undergoes a fundamental process of structural reorganization from an immature isotropic to a mature (adult) anisotropic architecture. However, the mechanism underlying this structural transformation is unknown. It could involve either an internal remodelling process, or complete resorption followed by tissue neoformation. The aim of this study was to establish which of these two alternative tissue reorganization mechanisms is physiologically operative. We also wished to pinpoint the articular cartilage source of the stem cells for clonal expansion and the zonal location of the chondrocyte pool with high proliferative activity.

METHODS: The New Zealand white rabbit served as our animal model. The analysis was confined to the high-weight-bearing (central) areas of the medial and lateral femoral condyles. After birth, the articular cartilage layer was evaluated morphologically at monthly intervals from the first to the eighth postnatal month, when this species attains skeletal maturity. The overall height of the articular cartilage layer at each juncture was measured. The growth performance of the articular cartilage layer was assessed by calcein labelling, which permitted an estimation of the daily growth rate of the epiphyseal bone and its monthly length-gain. The slowly proliferating stem-cell pool was identified immunohistochemically (after labelling with bromodeoxyuridine), and the rapidly proliferating chondrocyte population by autoradiography (after labelling with (3)H-thymidine).

RESULTS: The growth activity of the articular cartilage layer was highest 1 month after birth. It declined precipitously between the first and third months, and ceased between the third and fourth months, when the animal enters puberty. The structural maturation of the articular cartilage layer followed a corresponding temporal trend. During the first 3 months, when the articular cartilage layer is undergoing structural reorganization, the net length-gain in the epiphyseal bone exceeded the height of the articular cartilage layer. This finding indicates that the postnatal reorganization of articular cartilage from an immature isotropic to a mature anisotropic structure is not achieved by a process of internal remodelling, but by the resorption and neoformation of all zones except the most superficial (stem-cell) one. The superficial zone was found to consist of slowly dividing stem cells with bidirectional mitotic activity. In the horizontal direction, this zone furnishes new stem cells that replenish the pool and effect a lateral expansion of the articular cartilage layer. In the vertical direction, the superficial zone supplies the rapidly dividing, transit-amplifying daughter-cell pool that feeds the transitional and upper radial zones during the postnatal growth phase of the articular cartilage layer.

CONCLUSIONS: During postnatal development, mammalian articular cartilage fulfils a dual function, viz., it acts not only as an articulating layer but also as a surface growth plate. In the lapine model, this growth activity ceases at puberty (3-4 months of age), whereas that of the true (metaphyseal) growth plate continues until the time of skeletal maturity (8 months). Hence, the two structures are regulated independently. The structural maturation of the articular cartilage layer coincides temporally with the cessation of its growth activity--for the radial expansion and remodelling of the epiphyseal bone--and with sexual maturation. That articular cartilage is physiologically reorganized by a process of tissue resorption and neoformation, rather than by one of internal remodelling, has important implications for the functional engineering and repair of articular cartilage tissue.

PMID 17098451

Morphology and functional roles of synoviocytes in the joint

Arch Histol Cytol. 2000 Mar;63(1):17-31.

Iwanaga T, Shikichi M, Kitamura H, Yanase H, Nozawa-Inoue K. Source Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.


The joint capsule exhibits a unique cellular lining in the luminal surface of the synovial membrane. The synovial intimal cells, termed synoviocytes, are believed to be responsible for the production of synovial fluid components, for absorption from the joint cavity, and for blood/synovial fluid exchanges, but their detailed structure and function as well as pathological changes remain unclear. Two types of synoviocytes, macrophagic cells (type A cells) and fibroblast-like cells (type B cells) have been identified. Type A synoviocytes are non-fixed cells that can phagocytose actively cell debris and wastes in the joint cavity, and possess an antigen-presenting ability. These type A cells, derived from blood-borne mononuclear cells, can be considered resident macrophages (tissue macrophages) like hepatic Kupffer cells. Type B synoviocytes are characterized by the rich existence of rough endoplasmic reticulum, and dendritic processes which form a regular network in the luminal surface of the synovial membrane. Their complex three-dimensional architecture was first revealed by our recent scanning electron microscopy of macerated samples. The type B cells, which are proper synoviocytes, are involved in production of specialized matrix constituents including hyaluronan, collagens and fibronectin for the intimal interstitium and synovial fluid. The proliferative potentials of type B cells in loco are much higher than type A cells, although the transformation of subintimal fibroblasts into type B cells can not be excluded. In some mammals, type B cells show features suggesting endocrine and sensory functions, but these are not recognized in other species. The synoviocytes, which form a discontinuous cell layer, develop both fragmented basement membranes around the cells and junctional apparatus such as desmosomes and gap junctions. For an exact understanding of the mechanism of arthritis, we need to establish the morphological background of synoviocytes as well as their functions under normal conditions. PMID 10770586